The goal of the research proposal is to establish causality between genetic polymorphisms and mRNA expression patterns. A new method is developed which uses samples from two genetically distinct individuals. One first applies DNA array techniques to find genetic (genotype) and mRNA expression (phenotype) differences between these samples. One then tests for linkage between genotype and phenotype, resulting in a list of gene polymorphisms which co-inherit with specific mRNA expression differences. In this way, new regulators of transcription cascades may be identified. The current research proposal develops this method in a model system - the comparison of two strains of S. cerevisiae. Once it is shown to be a workable paradigm, the method will be directly applicable to many biological and biomedical problems. Comparison between disease and normal tissue, for example, may identify mutations in transcriptional regulators harbored by individuals with genetic diseases.